Methyl Isocyanate → 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide

HRID 410565Notes

Reaction equation

HRID 410565 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[OH:30][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][N:27]([C:42]([NH:41][CH3:40])=[O:43])[CH2:28][CH2:29]1

Participants

5

Reactant 3

HCID 12228Methyl IsocyanateHCID 81531DiisopropylethylamineHCID 584561264-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol

Product 1

HCID 584564224-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamideYield 63.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

4-[5-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidin-4-ol (Example 46, 50 mg, 0.115 mmol) was dissolved in CH2Cl2 (1 mL). N,N-diisopropylethyl-amine (30 μL, 0.172 mmol) and methyl isocyanate (7 μL, 0.130 mmol) were added sequentially. The solution was stirred overnight at rt, then concentrated in vacuo on a Genevac. The resultant residue was dissolved in DMSO and purified via HPLC (30-64% CH3CN:H2O) to provide 4-hydroxy-N-methyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]piperidine-1-carboxamide (36 mg, 0.073 mmol). MS ESI: [M+H]+ m/z 493.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 7.93 (s, 2H), 7.44 (s, 1H), 7.25 (d, J=5.1 Hz, 1H), 7.13 (s, 1H), 6.43 (d, J=4.8 Hz, 1H), 6.15 (s, 1H), 3.83-3.74 (m, 2H) (d, J=14.0 Hz, 2H), 3.07 (t, J=14.5 Hz, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.98-1.82 (m, 2H), 1.65 (d, J=13.9 Hz, 2H). rhSYK activity=+++

Workup

  1. concentrationconcentrated in vacuo on a Genevac
  2. dissolutionThe resultant residue was dissolved in DMSO
  3. custompurified via HPLC (30-64% CH3CN:H2O)

Sources & evidence

ORD record
ord-b05fef5da8bf42d9ad14fd71dafd0320
Source dataset
uspto-grants-2014_06
Patent number
US08759366B2

Reaction notes

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